NM_003611.3:c.1129+16A>G

Variant names:

• chrX-13753457-A-G
• rs3815049
• NM_003611.3:c.1129+16A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003611.3(OFD1):​c.1129+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,203,519 control chromosomes in the GnomAD database, including 34,154 homozygotes. There are 110,867 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (3488 hom., 9543 hem., cov: 22)
  • Exomes 𝑓: 0.28 (30666 hom. 101324 hem.)
• Consequence: OFD1 NM_003611.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.56
• Publications: 10 publications found

Genes affected

OFD1 (HGNC:2567): (OFD1 centriole and centriolar satellite protein) This gene is located on the X chromosome and encodes a centrosomal protein. A knockout mouse model has been used to study the effect of mutations in this gene. The mouse gene is also located on the X chromosome, however, unlike the human gene it is not subject to X inactivation. Mutations in this gene are associated with oral-facial-digital syndrome type I and Simpson-Golabi-Behmel syndrome type 2. Many pseudogenes have been identified; a single pseudogene is found on chromosome 5 while as many as fifteen have been found on the Y chromosome. [provided by RefSeq, Aug 2016]

OFD1 Gene-Disease associations (from GenCC):

• Joubert syndrome 10

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• OFD1-related ciliopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• orofaciodigital syndrome I

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 23

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Simpson-Golabi-Behmel syndrome type 2

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant X-13753457-A-G is Benign according to our data. Variant chrX-13753457-A-G is described in ClinVar as Benign. ClinVar VariationId is 94370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003611.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	NM_003611.3	MANE Select	c.1129+16A>G		intron	N/A	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.1129+16A>G		intron	N/A	NP_001427876.1
	OFD1	NM_001330209.2		c.1009+16A>G		intron	N/A	NP_001317138.1	O75665-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.1129+16A>G		intron	N/A	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.1009+16A>G		intron	N/A	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.1132+16A>G		intron	N/A	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 31892 AN: 110845 Hom.: 3480 Cov.: 22

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.300

GnomAD2 exomes AF: 0.348 AC: 63613 AN: 182729 AF XY: 0.339

Gnomad AFR exome AF: 0.280

Gnomad AMR exome AF: 0.650

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.314

GnomAD4 exome AF: 0.277 AC: 302121 AN: 1092621 Hom.: 30666 Cov.: 28 AF XY: 0.282 AC XY: 101324 AN XY: 358671

African (AFR) AF: 0.277 AC: 7289 AN: 26304

American (AMR) AF: 0.624 AC: 21946 AN: 35153

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 4787 AN: 19326

East Asian (EAS) AF: 0.444 AC: 13391 AN: 30130

South Asian (SAS) AF: 0.464 AC: 25028 AN: 53943

European-Finnish (FIN) AF: 0.255 AC: 10317 AN: 40469

Middle Eastern (MID) AF: 0.260 AC: 1058 AN: 4075

European-Non Finnish (NFE) AF: 0.245 AC: 205321 AN: 837309

Other (OTH) AF: 0.283 AC: 12984 AN: 45912

GnomAD4 genome AF: 0.288 AC: 31918 AN: 110898 Hom.: 3488 Cov.: 22 AF XY: 0.288 AC XY: 9543 AN XY: 33166

African (AFR) AF: 0.280 AC: 8544 AN: 30527

American (AMR) AF: 0.467 AC: 4871 AN: 10435

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 661 AN: 2636

East Asian (EAS) AF: 0.442 AC: 1553 AN: 3510

South Asian (SAS) AF: 0.456 AC: 1198 AN: 2629

European-Finnish (FIN) AF: 0.234 AC: 1379 AN: 5883

Middle Eastern (MID) AF: 0.278 AC: 60 AN: 216

European-Non Finnish (NFE) AF: 0.247 AC: 13060 AN: 52877

Other (OTH) AF: 0.305 AC: 460 AN: 1506

Alfa AF: 0.266 Hom.: 2736

Bravo AF: 0.312

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Joubert syndrome 10 (1)
-	-	1	Joubert syndrome;C1510460:Orofaciodigital syndrome I (1)
-	-	1	Orofaciodigital syndrome I (1)
-	-	1	Retinitis pigmentosa 23 (1)
-	-	1	Simpson-Golabi-Behmel syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.16
DANN	Benign	0.30
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3815049; hg19: chrX-13771576; COSMIC: COSV60794933;